Abstract
A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.
MeSH terms
-
Animals
-
Benzamides / chemical synthesis*
-
Benzamides / chemistry
-
Benzamides / pharmacology
-
Cells, Cultured
-
Combinatorial Chemistry Techniques
-
Hippocampus / cytology
-
Ion Channel Gating / drug effects
-
Neurons / drug effects
-
Neurons / physiology
-
Nicotinic Agonists / chemical synthesis*
-
Nicotinic Agonists / chemistry
-
Nicotinic Agonists / pharmacology
-
Patch-Clamp Techniques
-
Quinuclidines / chemical synthesis*
-
Quinuclidines / chemistry
-
Quinuclidines / pharmacology
-
Radioligand Assay
-
Rats
-
Receptors, Nicotinic / drug effects*
-
Receptors, Nicotinic / metabolism
-
Serotonin 5-HT3 Receptor Agonists
-
Stereoisomerism
-
Structure-Activity Relationship
-
alpha7 Nicotinic Acetylcholine Receptor
Substances
-
Benzamides
-
Chrna7 protein, rat
-
Nicotinic Agonists
-
Quinuclidines
-
Receptors, Nicotinic
-
Serotonin 5-HT3 Receptor Agonists
-
alpha7 Nicotinic Acetylcholine Receptor